Methods, compositions, and kits for organ protection during systemic anticancer therapy

ABSTRACT

Methods, compositions, and kits are presented for local tissue protection during systemic administration of anticancer therapeutic agents.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.10/684,203, filed Oct. 10, 2003, which is a continuation-in-part of U.S.application Ser. No. 10/364,383, filed Feb. 12, 2003, now abandoned,which claims the benefit of U.S. provisional application No. 60/355,764,filed Feb. 12, 2002, now expired, the disclosures of which areincorporated herein by reference in their entireties.

BACKGROUND OF THE INVENTION

Systemic administration of antineoplastic chemical agents has been amainstay of cancer treatment for the past 50 years. But despite successagainst an ever greater number of cancers, systemic administration ofthese toxic agents is often attended by deleterious side effects thatlimit their clinical usefulness.

For example, the antimetabolite fluorinated pyrimidines, among theearliest-introduced of the chemotherapeutic agents, remain front-linetreatment for a variety of cancers 40 years after their clinicalintroduction.

The prototype is 5-fluorouracil (5-FU), which is typically administeredparenterally, either by bolus or continuous infusion.

Oral administration of 5-FU is disfavored due to the high activity inthe gut wall of dihydropyrimidine dehydrogenase (DPD), the rate-limitingenzyme in 5-FU catabolism. To bypass this problem, orally administrablefluoropyrimidine derivatives have been developed, either in the form of5-FU precursors, or “prodrugs” (e.g., tegafur, Carmofur, capecitabine,and doxifluridine), or as coadministered combinations of prodrugs withDPD competitors or inhibitors (e.g. UFT, S-1, or Emitefur). Tegafur(FTORAFUR®) (1-(2-tetrahydrofuryl)-5-fluorouracil), is a congener offluorouracil that introduces a tetrahydrofuran residue in place of thedeoxyribose residue in the 5′-deoxy-5-fluorouridine (5′-FUDR) molecule.Carmofur, another orally administrable fluoropyrimidine prodrug, is1-hexylcarbamoyl-5-fluorouracil (also known as HCFU). Capecitabine(XELODA®, Roche Pharmaceuticals) is a rationally designedfluoropyrimidine carbamate prodrug of 5′-FUDR that can be given orally.

Metabolism of 5-FU and of its prodrugs is complex.

With reference to FIG. 1, tegafur, administered orally, is converted inthe liver to 5-fluorouracil (“FU”) by action of cytochrome P450.

Capecitabine is converted to 5-FU in a multistep process. In the liver,a 60 kDa carboxyesterase hydrolyzes much of the compound to5′-deoxy-5-fluorocytidine (5′-DFCR). Cytidine deaminase, an enzyme foundin most tissues, including tumors, subsequently converts 5′-DFCR to5′-deoxy-5-fluorouridine (5′-DFUR). The enzyme thymidine phosphorylase(TP) then hydrolyzes 5′-DFUR to the active drug 5-FU.

Within the cell, 5-FU can be converted to cytostatic (and/or cytotoxic)metabolites by any one or more of three main “anabolic” pathways, eachcatalyzed by a different enzyme. As labeled in FIG. 1, pathway 1involves the action of orotate phosphoribosyl transferase (OPRT),pathway 2 activates 5-FU via uridine phosphorylase (UP), and pathway 3requires the enzyme thymidine phosphorylase (TP). These three pathwaysinterconnect, converging on two principal mechanisms of cell toxicity.

In the first, circled and labeled “a” at the right of FIG. 1, 5-FU isultimately metabolized to 5-FUTP, which is incorporated duringtranscription into RNA. Currently, it is thought that the toxicityresults from the accumulation of fluorouracil residues in a wide varietyof mRNAs coding for many different proteins, rather than from alterationof any single cellular function.

The second principal mechanism of cell toxicity results from anabolicactivation of 5-FU to 5-FdUMP. As circled and labeled “b” in FIG. 1,5-FdUMP forms a ternary complex with thymidine synthase (TS) and thecofactor 5,10-methylene tetrahydrofolate (CH₂THF). Tight complexationsequesters TS; preventing the TS-mediated enzymatic formation of dTMP;this, in turn, decreases the synthesis, and thus availability, ofthymidine triphosphate (dTTP), which is required for DNA replication andrepair. Depletion of dTTP acts as a cytostatic brake on cell growth anddivision; more recently, it has been suggested that depletion of dTTPmay directly trigger programmed cell death (apoptotic) pathways.

Catabolic inactivation of 5-FU is conceptually simpler than anabolicactivation, with greater than 80% of an injected dose of 5-FU rapidlydegraded by a single pathway, the first and rate-limiting step of whichis catalyzed by dihydropyrimidine dehydrogenase (DPD) (also known,synonymously, as uracil reductase, dihydrouracil dehydrogenase, and asdihydrothymine dehydrogenase). The principal byproduct of catabolism,F-β-alanine, is circled and labeled “c” in FIG. 1.

Given the complex interrelatedness of the metabolic pathways, theclinical efficacy of 5-FU and its orally-administrable prodrugs depends,to a first, crude, approximation on the relative activities of theDPD-mediated catabolic pathway and each of the three principal anabolicpathways. But despite intensive study, the extent to which any of thesepathways predominates in human tumors is unknown and is likely to varyacross tumor types and with different modes and doses of drugadministration. Malet-Martino et al., The Oncologist 7:288-323 (2002);Ichikawa et al., Brit. J. Cancer 89:1486-1492 (2003)

The situation becomes more complex when considering the concurrent andinteracting effects of multiple, competing, substrates on the multipleand competing catabolic and anabolic enzymes in the fluoropyrimidinepathway. Further complexity is added by variation in the activity ofthese enzymes among a genetically diverse human population, with plasmalevels of 5-FU varying by about three orders of magnitude among humansexposed to the same dose of 5-FU.

UFT is a combination of uracil and ftorafur in a 4:1 molar ratio. UFT isapproved for clinical use in Europe and Japan; it has been denied FDAapproval for clinical marketing in the U.S.

After oral ingestion, the ftorafur component of UFT is metabolized byP450 to 5-FU. The uracil component is intended to compete with 5-FU fordegradation by DPD; present at a several-fold molar excess over ftorafurin the administered composition, and thus intended to be present at aseveral-fold molar excess over ftorafur (and thus 5-FU) in tissues,uracil is intended to outcompete 5-FU for reaction with DPD, inhibitingDPD catabolic inactivation of 5-FU. The intended result is a highercirculating level of 5-FU, leading to greater 5-FU-mediatedcytotoxicity. Cao et al., Clinical Cancer Res. 1:839-845 (1995).

But the actual in vivo concentrations of uracil and 5-FU after UFTadministration do not invariably follow the intended ratio.Administration of UFT to rats results in a greater than 1000-foldvariation in uracil level within various organs, and can lead to up to a100-fold excess of uracil over 5-FU in some tissues. (Kawaguchi et al.,Gann. 71(6):889-99. (1980)).

Furthermore, uracil can also compete with 5-FU for reaction with thethree principal anabolic activating enzymes. In order for the OFTcombination to show greater clinical efficacy than ftorafur alone,uracil must not outcompete 5-FU for activation by at least one of OPRT,TP, and UP in the tumor. The outcome thus depends upon the relativeamount of each of the four principal rate-limiting enzymes in each ofthe cells and tissues taking up 5-FU, and on the relative affinity ofeach of the enzymes for uracil and 5-FU. The latter depends, in turn, atleast in part on cellular pH: OPRT, for example, favors 5-FU over uracilby about 50 times at neutral pH.

Variation in the relative amounts of each of the four principalrate-limiting, enzymes among tissues and tumors makes a prioriprediction of UFT efficacy in any particular tumor unreliable. Andexperiments in laboratory animals provide little help: the relativeaffinities of these enzymes for 5-FU and for uracil differ substantiallyamong different animal species, and particularly among different animaltumors.

Sludden et al. report, for example, that liver DPD activity is highlyvariable within and among tested species. Sludden et al., Pharmacology56:276-280 (1998). At least one study reports that 5-fluorouracil is abetter substrate for human dihydrouracil dehydrogenase (DPD) than isuracil, Naguib et al., Cancer Research 45:5405-5412 (1985).

And as complex as the physiology of fluoropyrimidine metabolism may bewith respect to desired antitumor effects, the pathophysiology offluoropyrimidine side-effects is even less well understood.

Among these poorly understood side effects of fluoropyrimidineadministration, the physiology of hand-foot syndrome (“HFS”,“palmar-plantar erythrodysesthesia”, “PPES”) is perhaps the mostobscure.

HFS usually starts with numbness, tingling, redness, and painlessswelling of the hands and/or feet. Grade 1 HFS is characterized by anyof numbness, dysesthesia/parasthesia, tingling, and/or painless swellingor erythema of the distal extremities. Grade 2 is defined as painfulerythema of the hands and/or feet and/or discomfort affecting thepatient's activities of daily living. Grade 3 HFS is defined as moistdesquamation, ulceration, and blistering or severe pain of the handsand/or feet and/or severe discomfort that causes the patient to beunable to work or perform activities of daily living.

HFS is progressive with dose and duration of exposure tofluoropyrimidines. The FDA-approved XELODA® product insert reports a 54%-67% incidence of HFS irrespective of grade during treatment withcapecitabine at the FDA-approved dose, with a grade 3 incidence of11-17%. HFS is also seen in treatment with other chemotherapeuticagents, including antimetabolites such as cytarabine, and agents ofother classes, such as docetaxel and doxorubicin, including pegylatedliposomal forms of doxorubicin (CAELYX®).

The pathophysiology of hand-foot syndrome is as yet unknown andvariously ascribed to metabolites of 5-FU, local drug accumulation,increased levels of anabolic enzymes in the affected tissues, andvarious other factors. See, for example, Childress and Lokich, Amer. J.Clinical Oncology 26:435-436 (2003); Leo et al., J. Chemother. 6:423-426(1994); Elasmar et al., Jpn J. Clin. Oncol. 31:172-174 (2001); andFischel et al., “Experimental arguments for a better understanding ofhand-foot syndrome under capecitabine,” Proc. Amer. Ass'n Cancer Res.45:487 (abstract #2119) (March 2004).

In the face of such mechanistic uncertainty, the current standard ofpractice is to cease or attenuate the dose of fluoropyrimidine whenhand-foot syndrome develops. Unfortunately, the severity of hand-footsyndrome appears to correlate with tumor response, Chua et al.,“Efficacy of capecitabine monotherapy in patients with recurrent andmetastatic nasopharyngeal carcinoma pretreated with platinum-basedchemotherapy,” Proc. Am. Soc. Clin. Oncol. 22:511 (abstr. 2055) (2003);dose attenuation to reduce the symptoms of hand-foot syndrome thus alsoreduces efficacy of tumor treatment.

Topical treatment with DMSO, which has also been proposed, see U.S. Pat.No. 6,060,083, is not typically practiced in the clinic and is ofuncertain efficacy.

While hand-foot syndrome is common during capecitabine treatment, it israrely seen with the ftorafur-containing prodrug combinations UFT andS-1. S-1 lacks uracil yet, like UFT, causes hand-foot syndrome onlyrarely. The reason for the disparate prevalence is unknown, with theetiology of hand-foot syndrome with S-1 administration suggested todiffer from that seen with capecitabine and/or 5-FU. Elasmar et al., JpnJ. Clin. Oncol. 31:172-174 (2001).

Systemically-administered chemotherapeutic agents other thanfluoropyrimidine antimetabolites also cause side effects in variousorgans and tissues that are not involved in the disease being treated.Many of these agents interact with, and are metabolized by, complexmetabolic pathways.

There is thus a need in the art for compositions and methods forpreventing and/or treating side effects of systemically administeredchemotherapeutic agents.

There is a further need in the art for methods and compositions forpreventing and/or treating side effects of systemically administeredchemotherapeutic agents that neither abrogate nor attenuate thetherapeutic effect of the systemically administered agent, thuspermitting such chemotherapeutic agents to be used at therapeutic dosagelevels.

There is a particular need for methods and compositions for preventingand/or treating hand-foot syndrome, including methods and compositionsthat would obviate the withdrawal or attenuation of the dose ofsystemically administered chemotherapeutic agent, thus permittingsystemically administered chemotherapeutic agents, such asfluoropyrimidines, to be administered at therapeutic dosage levels.

SUMMARY OF THE INVENTION

The present invention solves these and other needs in the art byproviding methods, compositions, and kits for protecting desired organs,tissues, and/or cells (collectively hereinafter, “tissues”) from thetoxic effects of a systemically distributed toxic agent, such as asystemically administered chemical, biological, radiochemical, orradiobiological anticancer chemotherapeutic agent.

The method is based on the asymmetric delivery of the anticancertherapeutic agent and a tissue protectant to a subject, with theanticancer therapeutic agent delivered throughout the body, typically bysystemic administration, and the protectant vectored, or targeted, tothe tissue to be protected.

In a first set of embodiments, the protectant is administered so as toachieve high concentration at or within the tissue to be protected, withlow to negligible systemic distribution. In a second set of embodiments,the protectant is administered so as to reduce the concentration of theanticancer therapeutic locally at or within the tissue to be protected.In both cases, the protectant can serve to restore normal homeostasisprimarily, or exclusively, to the tissue to be protected.

In the first set of embodiments, the protectant is typicallyadministered locally, local administration being effective to establisha concentration of the protectant agent at the desired tissue that issufficient to protect the tissue from toxicity by the systemicallydistributed anticancer therapeutic agent. The route of administration ischosen or adapted so as additionally to constrain the circulatingconcentration of the protectant to levels that are insufficient toabrogate the clinical efficacy of the systemically distributedanticancer therapeutic agent or metabolite.

The spatial differential in concentration achieved in the methods of thepresent invention obviates the need to achieve a pharmacologicaldistinction between the agents, such as a difference in affinity for oneor more enzymes for which both agents serve as substrates. The methodsthus permit two agents having near-identical pharmacokinetics and/orenzyme specificity or affinity to serve, respectively, as the toxictherapeutic agent and as the protectant.

The spatially directed administration of the protectant allowsconcentrations of the protectant to be used that might be deleterious orharmful if achieved systemically. The methods also permit an agent to beused as a protectant that would, if administered systemically, diminishor abrogate the clinical efficacy of the systemically distributedanticancer therapeutic agent.

In embodiments of the methods of the present invention in which theprotectant agent is in current clinical practice, coadministered withthe toxic agent to achieve a systemic effect, the method comprisesdissociating the routes of administration of the two agents,administering the toxic agent by means sufficient to achieve systemicdistribution—such as by enteral or parenteral systemicadministration—and administering the protectant agent in a spatiallydirected fashion.

The protectant itself can usefully be a substrate, often biologicallyactive, for one or more enzymes involved in the metabolic activation ofthe systemically distributed toxic agent. The protectant, in otheralternative embodiments, can physically reduce, remove or inactive theanticancer therapeutic at the tissue or organ to be protected.

Accordingly, in a first aspect, the invention provides a method ofprotecting a desired body tissue from toxic effects of one or moresystemically distributed anticancer therapeutic agents or metabolitesthereof. The method comprises targeting one or more protectant agentsfor nonsystemic delivery to the tissue desired to be protected.

In a first series of embodiments, targeted nonsystemic deliverycomprises administering one or more protectant agents so as to establisha local concentration of the protectant agents in the tissue desired tobe protected that is sufficient to protect the tissue from the toxiceffects of the systemic agent. Administration is performed so asadditionally to ensure that the circulating concentration of theprotectant agents is insufficient to abrogate the clinical efficacy ofthe systemically distributed anticancer therapeutic agent or metaboliteat a tissue desired to be treated.

In typical embodiments, the systemically distributed anticancertherapeutic agent, or a metabolite or precursor thereof, is systemicallyadministered, for example by parenteral administration, such as byintravenous administration, or enteral administration, such as orally.

In these embodiments, typically the more protectant agents isadministered locally to the desired tissue, such as by topicaladministration to an integumentary surface, such as skin.

The timing of administration Of the protectant can vary.

In some embodiments, the one or more protectant agents is administeredbefore the at-risk tissue manifests toxic effects from the systemicallydistributed anticancer therapeutic agent or metabolite thereof, at timeseven before systemic administration of the anticancer therapeutic agent(or metabolite or precursor thereof). In various embodiments, the one ormore protectant agents is administered concurrently with systemicadministration of the anticancer therapeutic agent. In some embodiments,the protectant is administered before, during, and after systemicadministration of the anticancer therapeutic agent.

In the first series of embodiments of the methods of the presentinvention, the local concentration of each of the one or more protectantagents is at least about 5-fold greater than the circulatingconcentration of the protectant agent, often at least about 10-foldgreater than the circulating concentration of said protectant agent, attimes at least about 100-fold greater even at least about 1000-foldgreater than that in the circulation.

In some embodiments, at least one of the at least one protectant agentsinhibits in vivo activation of the systemically administered anticancertherapeutic agent or metabolite or precursor thereof, for example byinhibiting its anabolism. At least one of the at least one protectantagents can, for example, be a substrate for an enzyme involved inanabolic activation of the systemically administered anticancertherapeutic agent, or a metabolite or precursor thereof.

In other embodiments, at least one of the at least one protectant agentsfacilitates in vivo catabolism of the systemically administeredanticancer therapeutic agent, or a metabolite or precursor thereof.

The anticancer therapeutic agent, metabolite or precursor thereof, canbe an antimetabolite, such as a nucleotide, a nucleoside, or aderivative, analogue, or precursor thereof. For example, thesystemically distributed (typically, systemically administered)anticancer therapeutic agent can be ara-C (cytarabine) or afluoropyrimidine. The fluoropyrimidine can be parenterally administrablefluoropyrimidines and/or orally administrable.

In some embodiments, the fluoropyrimidine is 5-FU or a 5-FU prodrug suchas ftorafur, doxifluridine, and capecitabine. The systemicallyadministered fluoropyrimidine or fluoropyrimidine prodrug can becomposited with an inhibitor of dihydropyrimidine dehydrogenase (DPD).Among such compositions is a composition comprising ftorafur,5-chloro-2,4-dihydroxypyridine, and oxonic acid.

In other embodiments, the systemically distributed (typically,systemically administered) anticancer therapeutic agent, or metaboliteor precursor thereof, can be an anthracycline, or a topoisomerase Iinhibitor, or an antagonist of EGF or VEGF. For example, thesystemically distributed agent can be an anthracycline selected from thegroup consisting of doxorubicin, nonpegylated liposomal doxorubicin,pegylated liposomal doxorubicin, daunorubicin, liposomal daunorubicin,epirubicin, and idarubicin.

The systemically distributed (typically, systemically administered)anticancer therapeutic agent can be associated with toxicity to anepithelium, such as an integumentary or mucosal epithelium.

In certain embodiments, the toxicity is hand-foot syndrome. In theseembodiments, the protectant is usefully administered topically to thepalmar and/or plantar skin surface. In embodiments in which hand-footsyndrome is caused by systemic administration of a fluoropyrimidine,such as 5-FU or capecitabine, at least one of said at least oneprotectant agents is usefully uracil, usefully composited in ahydrophilic ointment for topical administration to the skin of the handsand feet.

In a second series of embodiments of the methods of the presentinvention, the targeted nonsystemic delivery of protectants comprisesadministering the protectant agent so as to effect a reduction, in thetissue desired to be protected, in the concentration of the systemicallydistributed anticancer therapeutic agent (or metabolite thereof) that issufficient to protect the tissue from the toxic effects of the systemicagent. The circulating concentration of the protectant agents isinsufficient to abrogate the clinical efficacy of the systemicallydistributed anticancer therapeutic agent or metabolite at a tissuedesired to be treated.

The methods of the present invention can sufficiently protect theat-risk tissue as to permit the full, unattenuated dose of anticancertherapeutic agent to be administered, with neither dose interruption,cessation, nor attenuation.

Thus, in a second aspect, the invention provides a method of treatingneoplasia.

The method comprises: systemically administering an anticancertherapeutic agent, or a precursor or metabolite thereof, to a subject inneed thereof; and concurrently targeting one or more protectant agentsfor nonsystemic delivery to the tissue desired to be protected by any ofthe methods above-described.

For example, the method can comprise the concurrent administration ofone or more protectant agents so as to establish a local concentrationof the protectant agents in the tissue desired to be protected that issufficient to protect the tissue from the toxic effects of the systemicagent. Administration is performed so as additionally to ensure that thecirculating concentration of the protectant agents is insufficient toabrogate the clinical efficacy of the systemically distributedanticancer therapeutic agent or metabolite at a tissue desired to betreated.

In other embodiments, the method can comprise the concurrentadministration of one or more protectant agents so as to effect areduction, in the tissue desired to be protected, in the concentrationof the systemically distributed anticancer therapeutic agent (ormetabolite thereof) that is sufficient to protect the tissue from thetoxic effects of the systemic agent. The circulating concentration ofthe protectant agents is insufficient to abrogate the clinical efficacyof the systemically distributed anticancer therapeutic agent ormetabolite at a tissue desired to be treated.

The systemically administered anticancer therapeutic agent, precursor ormetabolite thereof can be an antimetabolite, such a fluoropyrimidine,including parenterally administrable and orally administrablefluoropyrimidines, such as 5-FU, ftorafur, Carmofur, capecitabine,doxifluridine, UFT, S-1, or Emitefur.

In such embodiments, at least one of the at least one protectant agentsconcurrently administered with the fluoropyrimidine can be uracil. Theuracil can, for example, be administered topically to the plantar and/orpalmar skin surfaces.

In another aspect, the invention provides pharmaceutical compositionsfor local application to a body tissue, the composition capable ofestablishing a local concentration of one or more protectant agentssufficient to protect the tissue from toxic effects of one or moresystemically distributed anticancer therapeutic agents or metabolitesthereof without abrogating the clinical efficacy of said systemicallydistributed anticancer therapeutic agent or metabolite. The compositioncomprises at least one protectant agent; and a pharmaceuticallyacceptable carrier suitable for local application.

In some embodiments, at least one of the at least one protectants in thecomposition is uracil. Uracil can be present within the composition at aconcentration by weight of at least about 0.01%, often at least about0.1%; even at least about 1.0%. In various embodiments, uracil can bepresent within at a concentration by weight of no more than about 60%,often at a concentration of no more than about 5%.

In yet a further aspect, the invention provides kits for oral deliveryof an anticancer therapeutic agent or precursor (“prodrug”) thereof withreduced toxicity to a desired tissue.

The kit comprises at least one dose of an orally administrableanticancer therapeutic agent or precursor thereof; and at least one doseof a locally administrable tissue protectant composition. In someembodiments, the orally administrable anticancer therapeutic agent orprecursor is a fluoropyrimidine or fluoropyrimidine composition, such asftorafur, Carmofur, capecitabine, doxifluridine, UFT, S-1, or Emitefur.

In presently preferred kits, the fluoropyrimidine is capecitabine, theprotectant composition is suitable for topical delivery to the skin, andthe protectant composition comprises uracil. The uracil can usefully bepresent at a concentration by weight of at least about 0.1%, even atleast about 1.0%. The uracil can be present within the composition at aconcentration by weight of no more than about 60%, even no more thanabout 10%, with uracil usefully present in a weight percentage of about0.11%-10%, even 1%-5%.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and advantages of the present invention willbe apparent upon consideration of the following detailed descriptiontaken in conjunction with the accompanying drawings, in which likecharacters refer to like parts throughout, and in which:

FIG. 1 shows the basic metabolic pathways for anabolic activation andcatabolic degradation of fluoropyrimidines, as known in the art.

DETAILED DESCRIPTION

In a first aspect, the invention provides a method of protecting adesired organ or body tissue from toxic effects of one or more toxicagent, such as anticancer therapeutic agents, or metabolites thereof,that are systemically distributed through the body of subject, typicallya human patient undergoing chemotherapy for cancer.

The body tissue desired to be protected may be any body tissue that isnot intended to be treated by the systemically distributed anticancertherapeutic agent or anticancer therapeutic agent metabolite.

For example, in embodiments in which the patient is being treated forcancer, the body tissue desired to be protected would typically be onethat does not contain neoplastic cells. Analogously, in embodiments inwhich the patient is being treated with an anticancer therapeutic agent(or anticancer therapeutic agent metabolite) to effect myeloablation,for example to condition the patient prior to bone marrowtransplantation, the tissue desired to be protected may be any tissueother than the bone marrow.

The method comprises administering one or more protectant agents to thesubject.

In a first series of embodiments, the one or more protectant agents areso administered as to establish a local concentration of protectantagent in the organ, tissue, or cells (hereinafter, collectively“tissue”) desired to be protected that is sufficient to protect thetissue from the toxic effects of the systemically distributed toxicagent, such as a systemically distributed anticancer therapeutic agentor anticancer therapeutic agent metabolite, yet also constrain thecirculating concentration of protectant to levels that are insufficientto abrogate the clinical efficacy of the systemically distributedanticancer therapeutic agent or metabolite.

In a second series of embodiments, the one or more protectant agents areso administered as to lower the active concentration of the systemicallydistributed toxic agent (such as a systemically distributed anticancertherapeutic agent, or metabolite thereof) at or within the tissuedesired to be protected to a level that protects the tissue from thetoxic effects of the systemically distributed toxic agent, without,however, lowering the levels of the systemically distributed toxicagent, at the tissue desired to be treated, to levels that abrogate theclinical efficacy of the systemically distributed anticancer therapeuticagent or metabolite.

“Protection” intends a clinically observable decrease in one or moretoxic effects in the body tissue desired to be protected, as compared tothe toxic effects that would be seen absent the protectant.

Protection can be total, preventing all symptoms of toxicity in thedesired tissue; protection can be partial, reducing and/or delayingdevelopment of all or a subset of symptoms of toxicity in the desiredtissue. In some embodiments, protection is sufficient to permitadministration of the full dose and course of intended therapy withanticancer therapeutic agent or metabolite or precursor (prodrug)without dose cessation, dose attenuation, and/or alteration in dosageschedule. In some embodiments, protection is sufficient to allow anincrease in dose of the anticancer therapeutic agent or metabolite orprecursor.

The circulating concentration of the one or more protectants isconstrained to levels that are insufficient to abrogate the clinicalefficacy of the systemically distributed anticancer therapeutic agent ormetabolite thereof.

“Abrogate” intends a diminution in efficacy of the anticancertherapeutic agent (or metabolite thereof) at the tissue desired to betreated that is sufficiently great as to render therapy with theanticancer therapeutic agent or anticancer therapeutic agent metaboliteclinically ineffective or clinically inadvisable. In some embodiments,the circulating concentration of the one or more protectant agents issufficiently low as to cause no clinically observable diminution inpotency or efficacy of the systemically distributed anticancertherapeutic agent (or metabolite thereof) at the tissue desired to betreated, such as a tissue having neoplastic cells. In other embodiments,the circulating concentration of the one or more protectant agentscauses a clinically observable diminution in potency or efficacy of thesystemically distributed anticancer therapeutic agent (or metabolite) atthe tissue desired to be treated, but is insufficient to abrogate theclinical efficacy of the systemically distributed anticancer therapeuticagent or metabolite thereof.

In typical embodiments, the local concentration of the one or moreprotectants in the tissue desired to protected from toxic effects willbe greater than the concentration in the circulation. In someembodiments, the circulating concentration of the one or moreprotectants will be greater, in turn, than their concentration in thetissues desired to be treated with the systemically distributedanticancer therapeutic agent (such as a cancerous tissue).

In some embodiments, the local concentration of each of the one or moreprotectant agents in the tissue desired to be protected is at least5-fold greater than the circulating concentration of the protectantagent. In other embodiments, the local concentration is at least10-fold, at least 20-fold, at least 30-fold, at least 40-fold, at least50-fold or more greater than the concentration of the protectant in thecirculation. In various embodiments, the local concentration can be ashigh as at least 60-fold, 70-fold, 80-fold, 90-fold, even as high as100-fold or more greater than the concentration of the protectant in thecirculation. In some embodiments, the local concentration of protectantcan be as high as 1000-fold higher than in the circulation, or evenmore.

In various embodiments, the local concentration of protectant in thetissue desired to be protected is at least 10-fold, at least 20-fold, atleast 30-fold, at least 40-fold, at least 50-fold or more greater thanthe concentration of the protectant in the tissue desired to be treated.In various embodiments, the local concentration in the tissue desired tobe protected can be as high as at least 60-fold, 70-fold, 80-fold,90-fold, even as high as 100-fold or more greater than the concentrationof the protectant in the tissue desired to be treated. In someembodiments, the local concentration of protectant can be as high as1000-fold higher than in the tissue desired to be treated, or even more.The tissue desired to be treated can, e.g., be a tumor within a bodytissue or the entirety of a body tissue within which a portion of thecells are neoplastic.

Typically, the anticancer therapeutic agent or metabolite becomessystemically distributed upon or following systemic administration ofthe anticancer therapeutic agent, its metabolite, or a precursor thereofto the patient.

The anticancer therapeutic agent (or metabolite) can be achemical-agent, a biological agent, a radiochemical agent or aradiobiological agent that has antineoplastic activity.

In some embodiments, the anticancer therapeutic agent, metabolitethereof, or precursor thereof is administered parenterally, such as byintravenous infusion, either continuous or bolus infusion, byintramuscular injection, by subcutaneous injection, or by intrathecaladministration. In other embodiments, the anticancer therapeutic agent,metabolite thereof, or precursor thereof is administered orally. In yetother embodiments, the anticancer therapeutic agent, metabolite, orprecursor is administered by transepithelial means, as by anal orvaginal suppository. In yet other embodiments, the anticancertherapeutic agent, metabolite, or precursor is implanted into thepatient.

The systemically distributed anticancer therapeutic agent or metabolitecan be an antimetabolite such as a nucleotide, a nucleoside, or aderivative, analogue, or precursor thereof. For example, in certainembodiments, the systemically distributed anticancer therapeutic agentcan be a purine antimetabolite such as mercaptopurine, azathioprine,thioguanine, or fludarabine. In other embodiments, the systemicallydistributed anticancer therapeutic agent can be a pyrimidineantimetabolite such as ara-C (cytarabine), gemcitabine, azacitidine, ora fluoropyrimidine, or a metabolite thereof.

In some of these embodiments, the systemically distributed anticancertherapeutic agent is a fluoropyrimidine.

In certain of these embodiments, the fluoropyrimidine is a parenterallyadministrable fluoropyrimidine, such as 5-FU. In other embodiments, thefluoropyrimidine is an orally administrable fluoropyrimidine, such ascapecitabine, doxifluridine, or tegafur, alone or formulated inadmixture with one or more inhibitors of dihydropyrimidine dehydrogenase(DPD). In certain embodiments, for example, the fluoropyrimidine (suchas tegafur) can be administered in a composition that further comprisesuracil and/or 5-chloro-2,4-dihydroxypyridine, and optionally oxonicacid.

In other embodiments, the anticancer therapeutic agent is ananthracycline, or precursor or metabolite thereof. In some of theseembodiments, the anticancer therapeutic agent can be selected from thegroup consisting of doxorubicin, nonpegylated liposomal doxorubicin,pegylated liposomal doxorubicin, daunorubicin, liposomal daunorubicin,epirubicin, and idarubicin.

In other embodiments, the anticancer therapeutic agent can be a taxane,such as docetaxel or paclitaxel.

In typical embodiments, the one or more protectant agents isadministered locally to the tissue desired to be protected. In some suchembodiments, the one or more protectant agents is administered topicallyto the tissue desired to be protected. In other such embodiments, theone or more protectant agents is administered by local injection, suchas by local injection of depotized form of the one or more protectantagents.

In some embodiments of the methods of the present invention, the one ormore protectant agents is administered before the tissue desired to beprotected manifests toxic effects of the systemically distributedanticancer therapeutic agent or metabolite thereof.

Often, this prophylactic or preventative administration of the one ormore protectant agents is preferred. Such timing is particularlypreferred in embodiments in which the one or more protectant agents isto be administered to the skin as the tissue desired to beprotected—e.g. to prevent, ameliorate, delay, or treat hand-footsyndrome—because toxic side effects, once manifested in the skin, canincrease its permeability to, or otherwise increase its absorption of,the protectant, potentially increasing the circulating concentration ofthe protectant agent.

In certain of these embodiments, the one or more protectant agents isadministered before systemic administration of the anticancertherapeutic agent, metabolite thereof, or precursor thereof. In certainembodiments, the one or more protectant agents is administeredconcurrently with systemic administration of the anticancer therapeuticagent, metabolite thereof, or precursor thereof. In some embodiments,the one or more protectant agents is administered before and duringsystemic administration of the anticancer therapeutic agent, metabolitethereof, or precursor thereof. In yet other embodiments, the one or moreprotectant agents is optionally administered for a period followingcessation of systemic administration of the one or more anticancertherapeutic agents, or precursors, or metabolites thereof.

The protectant agent can, in some embodiments, be one that inhibits invivo activation of the systemically administered anticancer therapeuticagent, metabolite or precursor thereof.

For example, the protectant can in some embodiments inhibit anabolicactivation of a systemically administered anticancer therapeutic agent,metabolite, or precursor thereof. In some embodiments, the protectantagent can be a substrate, such as a competitive substrate, of an enzymeinvolved in anabolic activation of a systemically administeredanticancer therapeutic agent or metabolite or precursor thereof. Inembodiments in which the protectant acts as a substrate for an enzyme,the protectant agent can be a naturally-occurring compound.

In embodiments in which the systemically distributed anticancertherapeutic agent is a fluoropyrimidine, for example, the protectantagent can be a substrate, such as a competitive substrate, of an enzymeinvolved in anabolic activation of the systemically administeredfluoropyrimidine, such as a substrate for thymidine phosphorylase (TP),and/or uridine phosphorylase (UP), and/or orotate phosphoribosyltransferase (OPRT).

The protectant can, for example, be a naturally occurring compound, suchas a compound that serves as a substrate for any one or more of TP, UP,and OPT. The compound can be a naturally occurring nitrogenous base,such as a pyrimidine, including uracil. In other embodiments, thecompound can be a non-naturally occurring nitrogenous base, such as anonnaturally occurring pyrimidine.

Typically, the protectant will not act as an irreversible inhibitorof—or otherwise interfere with—an enzymatic activity or pathway in thecell, and thus will not occasion an imbalance in the absolute andrelative nucleotide concentrations within the cell.

In other embodiments, the protectant agent can be one that facilitatesin vivo catabolism of the systemically administered, anticancertherapeutic agent, metabolite, or precursor thereof.

In embodiments in which the systemically distributed anticancertherapeutic agent is a fluoropyrimidine, for example, the protectantagent can act to increase the amount or activity of dihydropyrimidinedehydrogenase (DPD) in the tissue desired to be protected.

For example, the protectant agent can include nucleic acids capable ofexpressing a protein, such as DPD, and can be administered, for example,by injection, as described, for example, in U.S. Pat. Nos. 5,580,859 and6,706,694, incorporated herein by reference in its entirety.

The protectant agent may be administered using a variety of dosageschedules designed to establish and maintain a local concentration inthe tissue desired to be protected that is sufficient to protect thetissue from the toxic effects of the systemically distributed anticancertherapeutic agent or anticancer therapeutic agent metabolite, yetconstrain the circulating concentration of protectant to levels that areinsufficient to abrogate the clinical efficacy of the systemicallydistributed anticancer therapeutic agent or metabolite.

The exact dosage schedule will depend, inter alia, on any one or more ofthe identity of the systemically distributed chemotherapeutic agent ormetabolite, the circulating concentration of chemotherapeutic agent ormetabolite, the tissue desired to be protected, the severity of sideeffects desired to be prevented or treated, and the formulation of theprotectant composition, particularly its concentration in the protectantcomposition; determination of the proper dosage schedule of protectantagent is within the skill of the clinical artisan.

For example, in embodiments of the methods of the present invention inwhich the protectant agent is administered topically to skin in anointment composition, the protectant can usefully be administered once aday, twice a day, three times a day, four times a day, or more times aday. As would be understood in the art, the composition can be appliedwith different dosage schedules to different tissues of a singlepatient. For example, the composition may be applied twice a day to theplantar surface of the feet, but applied more frequently to the hands,such as after each washing of the hands. The exact schedule may vary bypatient.

In some embodiments, the amount of protectant administered per dose isat least 0.01 g, 0.02 g, 0.03 g, 0.04 g, 0.05 g, 0.06 g, 0.07 g, 0.08 g,0.09 g, 0.1 g, 0.2 g, 0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g,1.0 g, 1.5 g, 2.0 g, 2.5 g, 3 g, 4 g, even 5 g or more, withintermediate values permissible. Typically, the amount of protectantadministered per dose is no more than about 10 g, 9 g, 8 g, 7 g, 6 g,even no more than about 5 g, 4.5 g, 4 g, 3.5 g, 3 g, 2 g, 1 g, and incertain embodiments even no more than about 0.5 g, 0.4 g, 0.3 g, 0.2 g,even no more than about 0.1 g.

For example, in embodiments of the methods of the present invention inwhich uracil as the protectant agent is administered two to four timesper day to the palmar and/or plantar surfaces of a patient undergoingsystemic administration of an anticancer therapeutic agent, prodrug ormetabolite thereof, such as systemic administration of afluoropyrimidine, such as 5-FU or capecitabine, the amount of uraciladministered per dose can usefully be at least about 0.01 g, 0.02 g,0.03 g, 0.04 g, 0.05 g, 0.06 g, 0.07 g, 0.08 g, 0.09 g, 0.1 g, 0.2 g,0.3 g, 0.4 g, 0.5 g, 0.6 g, 0.7 g, 0.8 g, 0.9 g, even at least 1.0 g,and typically no more than about 2.0 g, 1.5 g, 1.0 g, 0.9 g, 0.8 g, 0.7g, 0.6 g, 0.5 g, 0.4 g; 0.3 g, 0.2g, with a dose of 0.1 g currentlypreferred.

In another aspect, the invention provides protectant agents formulatedin compositions that permit local concentrations of protectant to beestablished that are sufficient to protect the tissue from the toxiceffects of the systemically distributed anticancer therapeutic agent oranticancer therapeutic agent metabolite, yet constrain the circulatingconcentration of protectant to levels that are insufficient to abrogatethe clinical efficacy of the systemically distributed anticancertherapeutic agent or metabolite.

Compositions of the present invention comprise one or more protectantagents and at least one pharmaceutically acceptable carrier orexcipient.

Each of the at least one protectant agents is typically present in theprotectant composition to a weight/weight percentage of at least 0.01%,0.05%, 1.0%, 1.5%, 2.0%, 2.5%, 3.5%, 4.0%, 4.5%, 5.0%,10%, 15%, 20%,25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, even 80% or more,with intermediate values permissible, and is typically present to aweight/weight percentage of no more than about 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4.5%, 4.0%, 3.5%,3.0%, 2.5%, 2.0%, 1.5%, 1.0%, and even, at times, to a weight/weightpercentage of no more than about 0.05%, even as little as 0.01%.

In embodiments of the compositions of the present invention comprising aplurality of protectant agents, typically the plurality of protectantsare cumulatively present to a weight/weight percentage of at least0.01%, 0.05%, 1.0%, 1.5%, 2.0%, 2.5%, 3.5%, 4.0%, 4.5%, 5.0%, 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, even 80% ormore, with intermediate values permissible, and is typically present toa weight/weight percentage of no more than about 80%, 75%, 70%, 65%,60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4.5%, 4.0%,3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%, 0.05%, even as little as 0.01%, withintermediate values permissible.

In embodiments that are presently preferred for protecting the palmarand/or plantar skin surfaces from hand-foot syndrome, such as duringsystemic administration of a fluoropyrimidine, an anthracycline, or ataxane anticancer therapeutic agent, or metabolite or precursor thereof,the compositions of the present invention typically comprise uracil asthe protectant agent, with the composition comprising uracil to aweight/weight percentage of at least 0.01%, 0.05%, 1.0%, 1.5%, 2.0%,2.5%, 3.5%, 4.0%, 4.5%, 5.0%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, even 80% or more, with intermediate valuespermissible; in such compositions, uracil is typically present to aweight/weight percentage of no more than about 80%, 75%, 70%, 65%, 60%,55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 4.5%, 4.0%, 3.5%,3.0%, 2.5%, 2.0%, 1.5%, 1.0%, and even, at times, to a weight/weightpercentage of no more than about 0.05%, even as little as 0.01%, withintermediate values permissible.

In presently preferred compositions for protecting the palmar and/orplantar skin surfaces, uracil is present to a weight/weight percentageof at least about 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%,even to a weight/weight percentage of at least about 1.0%, 1.1%, 1.2%,1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2.0%, 2.5%, 3.0% or more, withintermediate values permissible. In some embodiments, uracil is presentto a weight/weight percentage of at least about 3.5%, 4.0%, 4.5%, 5.0%,10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, even at least about60%, typically no more than about 60%, 55%, 50%, 45%, 40%, 35%, 30%,25%, 20%, 15%, 10%, 5%, 4.5%, 4.0%, 3.5%, 3.0%, 2.5%, 2.0%, 1.5%, 1.0%,0.05%, with intermediate values permissible. In certain usefulembodiments, uracil is present to a weight/weight percentage of about1%.

The exact formulation of the protectant agent compositions of thepresent invention will depend upon the identity of the tissue desired tobe protected. Pharmaceutical formulation is a well-established art, andis further described in Gennaro (ed.), Remington: The Science andPractice of Pharmacy, 20th ed., Lippincott, Williams & Wilkins (2000).(ISBN: 0683306472); Ansel et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, 7th ed., Lippincott Williams & Wilkins Publishers(1999) (ISBN: 0683305727); and Kibbe (ed.), Handbook of PharmaceuticalExcipients American Pharmaceutical Association, 3rd ed. (2000) (ISBN:091733096X), the disclosures of which are incorporated herein byreference in their entireties.

In embodiments in which the tissue desired to be protected is the skin,for example, the one or more protectant agents will typically beformulated for localized, typically topical, administration to the skinsurface. In embodiments in which the patient is being treatedsystemically with a fluoropyrimidine, an anthracycline, or a taxaneanticancer therapeutic agent, or precursor or metabolite thereof, forexample, the one or more protectant agents Will often be formulated fortopical administration to the palmar and plantar skin surfaces.

Compositions of the present invention intended for topicaladministration to the skin may, for example, be anhydrous, aqueous, orwater-in-oil or oil-in-water emulsions. Emulsions are presentlypreferred. Compositions of the present invention may further include oneor more pharmaceutically acceptable carriers or excipients and variousskin actives. Amounts of the carrier may range from about 1 to about99%, preferably from about 5 to about 70%, optimally from about 10 toabout 40% by weight. Among useful carriers are emollients, water,inorganic powders, foaming agents, emulsifiers, fatty alcohols, fattyacids, and combinations thereof.

Emollients can be selected from polyols, esters and hydrocarbons.

Polyols suitable for the invention may include propylene glycol,dipropylene glycol, polypropylene glycol, polyethylene glycol, sorbitol,hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,1,2,6-hexanetriol, glycerin, ethoxylated glycerin, propoxylatedglycerin, xylitol and mixtures thereof

Esters useful as emollients include alkyl esters of fatty acids having10 to 20 carbon atoms. Methyl, isopropyl, and butyl esters of fattyacids are useful herein. Examples include hexyl laurate, isohexyllaurate, isohexyl palmitate, isopropyl palmitate, decyl oleate, isodecyloleate, hexadecyl stearate, decyl stearate, isopropyl isostearate,diisopropyl adipate, diisohexyl adipate, dihexyldecyl adipate,diisopropyl sebacate, lauryl lactate, myristyl lactate, and cetyllactate. Particularly preferred are C12-C15 alcohol benzoate esters.

Esters useful as emollients also include alkenyl esters of fatty acidshaving 10 to 20 carbon atoms. Examples thereof include oleyl myristate,oleyl stearate and oleyl oleate.

Esters useful as emollients also include ether-esters such as fattyacids esters of ethoxylated fatty alcohols.

Esters useful as emollients also include polyhydric alcohol esters.Ethylene glycol mono and di-fatty acid esters, diethylene glycol mono-and di-fatty acid esters, polyethylene glycol (200-6000) mono- anddi-fatty acid esters, polyglycerol poly-fatty esters, ethoxylatedglyceryl monostearate, 1,3-butylene glycol monostearate, 1,3-butyleneglycol distearate, polyoxyethylene polyol fatty acid ester, sorbitanfatty acid esters, and polyoxyethylene sorbitan fatty acid esters aresatisfactory polyhydric alcohol esters.

Esters useful as emollients additionally include wax esters such asbeeswax, spermaceti, myristyl myristate, stearyl stearate.

Esters useful as emollients still further include sterol esters, ofwhich cholesterol fatty acid esters are examples thereof.

Illustrative hydrocarbon carriers are mineral oil, polyalphaolefins,petrolatum, isoparaffin, polybutenes and mixtures thereof.

Inorganic powders are also useful as carriers in the compositions of thepresent invention. Examples include clays (such as Montmorillonite,Hectorite, Laponite and Bentonite), talc, mica, silica, alumina,zeolites, sodium sulfate, sodium bicarbonate, sodium carbonate, calciumsulfate and mixtures thereof.

The compositions of the present invention can also include aerosolpropellants, serving as, or in addition to, carriers or excipients.Propellants can be based on volatile hydrocarbons such as propane,butane, isobutene, pentane, isopropane and mixtures thereof. PhilipsPetroleum Company is a source of such propellants under trademarksincluding A31, A32, A51 and A70. Halocarbons including fluorocarbons arefurther widely employed propellants.

The compositions of the present invention, particularly embodimentsformulated for administration to the skin, can comprise emulsifiers,either serving as, or in addition to, carriers or excipients.

Emulsifiers may be selected from nonionic, anionic, cationic, oramphoteric emulsifying agents. They may range in amount anywhere fromabout 0.1 to about 20% by weight.

Illustrative nonionic, emulsifiers are alkoxylated compounds based onC10-C22 fatty alcohols and acids and sorbitan. These materials areavailable, for instance, from the Shell Chemical Company under theNeodol trademark. Copolymers of polyoxypropylenepolyoxyethylene sold bythe BASF Corporation under the Pluronic trademark are sometimes alsouseful. Alkyl polyglycosides available from the Henkel Corporation mayalso be utilized for purposes of this invention.

Anionic type emulsifiers include fatty acid soaps, sodium laurylsulfate, sodium lauryl ether sulfate, alkyl benzene sulphonate, mono-and di-alkyl acid phosphates, sarcosinates, taurates and sodium fattyacyl isethionate.

Amphoteric emulsifiers useful in the compositions of the presentinvention include such materials as dialkylamine oxide and various typesof betaines (such as cocamidopropyl betaine).

The compositions of the present invention can also includepreservatives, such as methyl paraben and propyl paraben are useful toprevent microbial contamination.

In embodiments of the compositions of the present invention formulatedfor topical application to skin, the composition can usefully beformulated as an ointment, a cream, a lotion, a paste, an aerosol spray,a roll-on liquid, stick, or pad, or an aerosol foam (mousse)composition.

For example, mousse compositions of the present invention can bequick-breaking or slow-breaking foams, such as those described in U.S.Pat. Nos. 6,730,288, 6,627,585, 6,589,518, 6,395,258, 6,383,472,6,113,888, 6,113,881, 6,080,392, 5,783,202, the disclosures of which areincorporated herein by reference in their entireties.

In one embodiment, the composition is a hydrophilic ointment comprisinguracil as the protectant agent, and further comprising methyl paraben,propylparaben, sodium lauryl sulfate, propylene glycol, sterol alcohol,white petrolatum, water and light mineral oil.

In embodiments in which the tissue desired to be protected is themucosal epithelium of the mouth, as in chemotherapy-induced stomatitis,the protectant agents can be applied to the oral cavity in the form of atopical formulation. In methods of the present invention for protectingmucosal epithelium from the toxic effects of a systemically distributedanticancer therapeutic agent or metabolite thereof, care is typicallytaken to prevent or to reduce oral ingestion.

Formulations suitable for topical oral application include oralemulsions, magmas, gels, swishes, lozenges, pastes, creams, oralsolutions, gums, etc., as are well known in the art. Any of thesetopical oral vehicles can be used in conjunction with the methods of theinvention. Exact formulations, as well as methods of their preparation,will be apparent to those of skill in the art.

In one embodiment of a composition of the present invention useful fortopical delivery to the mucosal epithelium of the mouth, the one or moreprotectant agents are administered in a topical gel-like formulationcomprising a gel-like vehicle. The gel-like vehicle generally comprisesa water-soluble gelling agent, a humectant and, water, and has aviscosity of about 500 to 100,000 cps, preferably about 10,000 to 50,000cps, more preferably about 15,000 to 30,000 cps and most preferablyabout 20,000 to 25,000 cps as measured with a Brookfield viscometer atabout 25° C. The gelling agent provides the formulation with goodmucoadhesion properties; the humectant with good moisturizing andmoisture-barrier properties.

Gelling agents suitable for use with the vehicle of the inventioninclude, e.g., agar, bentonite, carbomer (e.g., carbopol), water solublecellulosic polymers (e.g., carboxyalkyl cellulose, hydroxyalkylcellulose, alkyl cellulose, hydroxyalkyl alkylcellulose), povidone,kaolin, tragacanth and veegum, with hydroxylalkyl alkyl celluloses suchas hydroxypropyl methylcellulose being preferred.

Humectants suitable for use with the gel-like vehicle of the inventioninclude, e.g., glycerin, propylene glycol and sorbitol, with sorbitolbeing preferred.

Generally, the vehicle comprises about 0.1% (w/w) to 10% (w/w)water-soluble gelling agent, with about 0.25% (w/w) to 5% (w/w) beingpreferred and about 0.5% (w/w) to 3% (w/w) being most preferred andabout 0.1% (w/w) to 20% (w/w) humectant. However as the viscosity of thegel-like vehicle is of considerable importance, it will be understoodthat the above concentration ranges are for guidance only. The actualconcentration of gelling agent will depend, in part, on the polymerselected, the supplier and the specific lot number. The actualconcentrations of other ingredients will likewise affect the viscosityof the gel-like formulation. Choosing appropriate concentrations toyield a gel-like formulation with the desirable viscosity and otherproperties described herein is within the capabilities of ordinarilyskilled artisans.

Additionally, the gel-like vehicle of the invention may includeantimicrobial preservatives. Antimicrobial preservatives useful with thecompositions of the invention include, but are not limited to,antifungal preservatives such as benzoic acid, alkylparabens, sodiumbenzoate and sodium propionate; and antimicrobial preservatives such asbenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal, with alkylparabens such asmethylparaben, propylparaben and mixtures thereof being preferred.

An amount of antimicrobial preservative(s) effective for use with theformulations of the invention will be apparent to those of skill in theart and will depend, in part, on the antimicrobial agent(s) used.Typical concentrations range from about 0.01% (w/w) to about 2% (w/w).

The composition of the invention formulated for topical administrationto the oral mucosa may also contain from about 1% (w/w) to 10% (w/w) ofa sweetening agent such as aspartame, dextrose, glycerin, malitol,mannitol, saccharin sodium, sorbitol, sucrose and xylitol. Suchsweetening agents are believed to aid patient compliance.

The pH of the composition will depend on the tissue protectant(s)contained in the composition. Determination of an optimal pH forstability and efficacy is well within the skill of the ordinary artisan.

Other optional ingredients that can be used without deleteriouslyaffecting, and in some cases even enhancing, the efficacy of theformulations of the invention adapted for mucosal, notably oral mucosal,delivery, include, but are not limited to, acidifying agents such asacetic acid, citric acid, fumaric acid, hydrochloric acid, lactic acidand nitric acid; alkalinizing agents such as ammonia solution, ammoniumcarbonate, diethanolamine, monoethanolamine, potassium hydroxide, sodiumborate, sodium carbonate, sodium hydroxide, triethanolamine andtrolamine; buffering agents such as potassium metaphosphate, potassiumphosphate, sodium acetate and sodium citrate; antioxidants such asascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylatedhydroxytoluene, hypophosphorous acid, monothioglyceride, propyl gallate,sodium ascorbate, sodium bisulfite, sodium formaldehyde sulfoxylate andsodium metabisulfite; chelating agents such as edetate disodium andedetic acid; colorants such as FD&C Red No. 3, FD&C Red No. 20, FD&CYellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5,caramel and ferric oxide, red; and flavoring agents such as anise oil,cinnamon oil, cocoa, menthol, orange oil, peppermint oil vanillin.Suitable concentrations for use will be apparent to those of skill inthen art. Other optional ingredients, as well as suitable concentrationsfor use, can be found, for example, in Gennaro (ed.), Remington: TheScience and Practice of Pharmacy, 20th ed., Lippincott, Williams &Wilkins (2000) (ISBN: 0683306472).

In embodiments of the methods of the present invention in which thetissue desired to be protected is rectal or colonic mucosa—typically,embodiments in which the systemically distributed anticancer therapeuticagent or precursor or metabolite thereof is administered to treat acondition other than colorectal carcinoma—the protectant compositions ofthe present invention can be formulated for administration by enema.

The compositions of the present invention may be packaged for single useor multiple use, with multiple use packaging usefully designed toprovide protectant composition sufficient for the duration of aconcurrent course of systemic therapy with anticancer therapeutic agent.

For example, a uracil ointment useful in protecting palmar and plantarsurfaces from the toxic effects of systemically distributedfluoropyrimidine or metabolite or prodrug thereof, may usefully bepackaged in an amount sufficient for at least a 14-day or 21-day course.

The compositions of the present invention can also usefully be packagedin kits.

The kits of the present invention can, for example, usefully comprise aprotectant composition and an orally administrable anticancertherapeutic agent or precursor.

In some embodiments, the invention can comprise a protectant compositionformulated for application to a skin surface, such as the palmar and/orplantar skin surface, and an orally administrable fluoropyrimidine, suchas tegafur, Carmofur, capecitabine, doxifluridine, UFT, S-1, orEmitefur. In such embodiments, the kit can comprise a plurality of dosesof orally administrable fluoropyrimidine, usefully a sufficient numberof doses for a standard course of therapy, and a sufficient amount ofprotectant composition for administration during the course of oralchemotherapy. The plurality of doses of orally administrablefluoropyrimidine can be ganged together, for example in one or moreblister packs.

In some of these embodiments, the protectant composition of the kitcomprises uracil as the protectant; in certain of these embodiments,uracil is present in a weight/weight percentage of 1.0%.

Embodiments of the kits of the present invention can optionally, butusefully, comprise applicators, particularly in embodiments in which theprotectant composition is intended for local administration to a tissueother than the skin surface.

Kits will typically also include instructions for administration of theprotectant composition and, if the kit comprises an orally administrableanticancer therapeutic agent or precursor, instructions for oraladministration of the oral agent.

In some embodiments, the kits can include dressings, such as occlusivedressings, that facilitate the establishment of a sufficient localconcentration of the protectant composition.

The following examples are offered by way of illustration only, and notby way of limitation.

EXAMPLE 1

The theoretical systemic exposure to uracil from the topical applicationof a 1% w/w uracil ointment to the hands and feet can be crudelyestimated as follows.

Application of 0.1 gm of a 1% (w/w) uracil ointment to the hands andfeet four times a day represents an exposure of 4-8 mg of uracil/day.The topical absorption of agents through intact skin can be on the orderof 1%, leading to a systemic absorption of 40-80 μg/day. This contrastswith exposure of about 1200 mg/day of uracil in UFT. Thus, the meansystemic uracil exposure with uracil ointment averages about 0.00005(0.005%) that of UFT.

At the skin surface, however, and in the underlying skin, theconcentration of uracil should be about 10 mg/ml. The average plasma5-FU concentration is usefully estimated at 0.5 μg/ml. Thus, topicaladministration of uracil ointment theoretically establishes a localconcentration of uracil that is approximately 2000-fold that of 5-FU atthe skin, with a systemic dose only 0.005% that occasioned by oraladministration of UFT.

EXAMPLE 2

A 48 year old female patient exhibited metastatic breast cancer. She hadrefused mastectomy and had previously failed adriamycin and cytoxin,weekly taxol, and weekly navelbine. She was then placed on Xeloda®together with 1% uracil ointment applied to the hands and feet. The 1%uracil ointment was used starting with cycle 5 of treatment withXeloda®.

Table 1 below summarizes results on this patient.

TABLE 1 Course q3wk 1 2 3 4 5 6 7 8 Xeloda 1250 mg/m² Same D/C 1000mg/m² 1250 mg/m² Same Same Same dose bid × after 4 bid × bid × 14 14/2114 days 14 days Taxotere + + + + + + + + 75 mg/m² Marker 12 × 12 8 × 8 7× 7 7 × 7 9 × 9 8.5 × 8 × 8 8.5 × tumor progression 8.5 8.5 size cm- onlower prior to dose rx Xeloda ® 1% 0 0 0 0 + + + + uracil ointment Hand-ND* ND ++++ ++ 0 0 0 0 foot syndrome *ND: Not described

The 1% uracil ointment allowed a re-escalation of the dose of Xeloda®with anti-tumor activity at the higher dose of Xeloda®. The 1% uracilointment allowed a higher dose-of Xeloda® to be administered withimproved anti-cancer efficacy (compare columns 5 and 6). The 1% uracilointment did not have any discernible toxicity.

EXAMPLE 3

Another patient, a 68 year old white female diagnosed with metastaticcolon cancer, was treated with Xeloda® and thalidomide. Hand-FootSyndrome developed. Complete reversal of the syndrome occurred aftertopical treatment with a 1% uracil ointment. The efficacy of the Xeloda®and thalidomide treatment was unaffected by the concurrent use of 0.1 g1% uracil ointment four times a day. There were no dose reductions ofchemotherapy or treatment delays.

EXAMPLE 4

A 60 year old white female with metastatic colon cancer was treated with5-FU, Leucovorin®, and Oxaliplatin, a common regime of treatment forthis form of cancer. The patient developed hand-foot syndrome.

Topical application of 0.1 g of 1% uracil ointment four time per dayresulted in complete resolution of the syndrome. The anti-cancertreatment remained efficacious. No side-effects were noted as a resultof the uracil ointment applications. There were no dose reductions ofchemotherapy or treatment delays.

In total, 7 patients have been treated with 1% uracil ointment. In nocase did hand-foot syndrome develop; there was no observable toxicreaction to the 1% uracil ointment.

EXAMPLE 5

A patient with EGFR-expressing metastatic colorectal carcinomaundergoing systemic treatment with cetuximab (ERBITUX®) as single agenttherapy develops dermatological toxicity, including skin drying andfissuring and acneform rash.

Cetuximab is a recombinant, human/mouse chimeric monoclonal antibodythat binds specifically to the extracellular domain of the humanepidermal growth factor receptor (EGFR), competitively inhibiting thebinding of epidermal growth factor (EGF) and other ligands, such astransforming growth factor-α.

The patient is treated topically at the site of skin toxicity with 10%EGF (recombinant) in ointment formulation two to four times a day, withreversal of skin toxicity manifestations, permitting the full andunattenuated course of cetuximab to be administered. Systemic absorptionof EGF from the topical application of ointment has negligible effect onclinical efficacy of cetuximab therapy.

EXAMPLE 6

A patient being treated with 5-FU by infusion according to the RoswellPark regimen develops diarrhea. The GI toxicity is presumed to resultfrom the local activation of 5-FU by OPRT in the gut.

The patient is treated orally with a daily mixture of 10 mg of orotatetogether with 10 mg adenine in a slow release capsule formulation;diarrhea is reduced. Orotate, the natural substrate for OPRT, has abouta 50-fold lower Km for OPRT than 5-FU at neutral pH. Adenine is includedto balance purine (adenine) and pyrimidine (orotate) administration andsynthesis. The change in systemic concentration of orotate and adenineis negligible.

EXAMPLE 7

A patient is being treated with bevacizumab (AVASTIN™) in combinationwith intravenous5-fluorouracil-based for metastatic carcinoma of thecolon. Bevacizumab is a recombinant humanized monoclonal IgG1 antibodythat binds to and inhibits the biologic activity of human vascularendothelial growth factor (VEGF).

The patient manifests skin toxicity.

A 1% w/v formulation of VEGF (recombinant) in an ointment formulation isapplied to the affected skin areas two to four times per day, withresolution of the skin toxicity and negligible effect on the systemicconcentration of VEGF.

EXAMPLE 8

A patient being treated with CPT-11 (CAMPTOSAR®, Irinotecan) for therapyof metastatic colorectal carcinoma manifests serious diarrhea as a toxicside effect of chemotherapy. Irinotecan and its active metabolite SN-38bind to the topoisomerase I-DNA complex and prevent religation ofsingle-strand breaks.

Aliquots of a mixture of plasmid DNA and topoisomerase I protein aresealed in dialysis membranes having MW cutoff sufficient to retain theprotein/DNA complex and admit CPT-11. The patient ingests (withoutchewing) one such dialysis tubing twice per day, with significantreduction in diarrhea, due to partition of CPT-11 and/or SN38, theactive metabolite, into the sealed dialysis membrane, reducing the levelof CPT-11 to which the gastrointestinal mucosa is exposed. The reactionbetween SN38 and topoisomerase I and DNA requires only magnesium.

All patents, patent publications, and other published referencesmentioned herein are hereby incorporated by reference in theirentireties as if each had been individually and specificallyincorporated by reference herein.

While specific examples have been provided, the above description isillustrative and not restrictive. Any one or more of the features of thepreviously described embodiments can be combined in any manner with oneor more features of any other embodiments in the present invention.Furthermore, many variations of the invention will become apparent tothose skilled in the art upon review of the specification. The scope ofthe invention should, therefore, be determined by reference to theappended claims, along with their full scope of equivalents.

1-71. (canceled)
 72. A topical formulation consisting of an emulsion ofabout 1% (w/w) uracil and one or more pharmaceutically acceptablecarriers.
 73. The topical formulation of claim 72, wherein thepharmaceutically acceptable carrier is a water-in-oil or oil-in-wateremulsion.
 74. The topical formulation of claim 73, wherein the emollientcomprises polyols, esters, hydrocarbons, and mixtures thereof.
 75. Thetopical formulation of claim 73, wherein the polyols comprise propyleneglycol, dipropylene glycol, polypropylene glycol, polyethylene glycol,sorbitol, hydroxypropyl sorbitol, hexylene glycol, 1,3-butylene glycol,1,2,6-hexanetriol, glycerin, ethoxylated glycerin, propoxylatedglycerin, xylitol and mixtures thereof.
 75. The topical formulation ofclaim 73, wherein the esters comprise alkyl esters of fatty acids having10 to 20 carbon atoms.
 76. A method of treating skin surfaces of a humansuffering from the adverse effects of one or more systemicallydistributed anticancer therapeutic agents or metabolites comprised offluorouracil or a prodrug thereof without abrogating the clinicalefficacy of said systemically distributed anticancer therapeutic agentor metabolite, comprising: administering a formulation comprising uracilto the skin surfaces in an amount effective to protect against theadverse effects of one or more systemically distributed anticancertherapeutic agents or metabolites thereof.
 77. The method of claim 76,wherein the skin surface is the palmar surface.
 78. The method of claim76, wherein the skin surface is the plantar surface.
 79. The method ofclaim 76, wherein the amount of uracil effective to protect against theeffects of one or more systemically distributed anticancer therapeuticagents or metabolites thereof is at a amount by weight of least about0.01% and less than about 20%.
 80. The method of claim 76, wherein theamount of uracil effective to protect against the effects of one or moresystemically distributed anticancer therapeutic agents or metabolitesthereof is at a amount by weight of least about 0.01% and less thanabout 10%.
 81. The method of claim 76, wherein the amount of uracileffective to protect against the effects of one or more systemicallydistributed anticancer therapeutic agents or metabolites thereof is at aamount by weight of least about 0.01% and less than about 5%.
 82. Themethod of claim 76, wherein the amount of uracil effective to protectagainst the effects of one or more systemically distributed anticancertherapeutic agents or metabolites thereof is at a amount by weight ofleast about 0.01%.
 83. The method of claim 76, wherein the amount ofuracil effective to protect against the effects of one or moresystemically distributed anticancer therapeutic agents or metabolitesthereof is at a amount by weight of least about 0.1%.
 84. The method ofclaim 76, wherein the amount of uracil effective to protect against theeffects of one or more systemically distributed anticancer therapeuticagents or metabolites thereof is at a amount by weight of least about1%.